Concept of oncolytic virotherapyclinical

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1 Concept of oncolytic virotherapyclinical implementation Simona Donina A. Kirchenstein Institute of Microbiology and Virology, Riga Stradiņš University Riga East University Hospital

2 Timeline of the clinical history of oncolytic viruses Ta-Chiang Liu et al.,nature Clinical Practice Oncology 2007

3 A. Complete regression of Burkitt's lymphoma over 2 weeks in a patient experiencing acute measles infection. B. Complete hematologic response of chronic lymphocytic leukemia following patient vaccination with vaccinia and subsequent virus dissemination. Permission obtained from Elsevier Bluming AZ and Ziegler JL (1971) Lancet 2 and from American Medical Association Hansen RM and Libnoch JA (1978) Arch Intern Med Nature Clinical Practice Oncology 2007

4 Advantages of oncolytic virotherapy L Braidwood et al., Oncolytic Virotherapy 2013:2 Feature Replicates within tumor cells to increase viral dose Replicates only within tumor cells Can be used safely with other cancer treatments and may have synergistic effect Can also be engineered or armed to carry a wide variety of transgenes to enhance the therapeutic effect such as prodrugs or inducers of immunological response Some evidence that ohsv are capable of targeting and eliminating cancer stem cells Advantage Amplification leads to oncolysis in cells beyond those initially infected Increases therapeutic index Minimal toxicity to normal tissues Dual effect of viral oncolysis and the added effect of the prodrug or immune stimulator Eliminates the population of cells that are often resistant to chemotherapy and radiotherapy

5 Infection and killing of tumor cells by oncolytic viruses Selective targeting to tumor cells innate properties of native viral particles engineered viruses through deletion of nonessential viral genes or insertion of tumor targeting sequences to provide the virus with the property of tumor-selective infection Ability to induce tumor cell lysis Induction of local and systemic antitumor immune respons expression of viral proteins and release of antigens eventually also leads to immune-mediated lysis of infected cells by CD8 + cells. T Hughes et al, Oncolytic Virotherapy 2014

6 Infection and killing of tumor cells by oncolytic viruses L Aurelian et al., Oncolytic Virotherapy 2013 Increased binding to altered target Replication/intratumoral spread Cell lysis/antigen release/immune response/virus spread Reduced target binding Virus does not replicate Healthy tissue undamaged

7 The immune response to oncolytic virotherapy is an essential factor determining the success of virus as an antitumor agent NK B Mf Tc Th

8 Hypothesis... During the virotherapy downregulate early innate immune response in order to allow the virus longer to enter cells and undergo initial viral replication upregulate later cellular immune response to make infected tumor cells more likely targeted for destruction by immune system L Aurelian et al., Oncolytic Virotherapy 2013

9 The oncolytic virotherapy paradigm

10 Barriers to optimal delivery of oncolytic viruses to tumours in vivo Kelley A et al., Nature Reviews Cancer 2005

11 Challenges Bazan-Peregrino M, et al., J Control Release Miller CG et al., Mol Ther Benencia F et al., Hum Gene Ther J Goldufsky et al, Oncolytic virotherapy 2014 Increasing the replicative capacity of the virus within cancer cells Alteration of the microenvironment (inhibition of angiogenesis) Combination with chemo- and immunotherapy Avoidance of neutralizing antibodies

12 April 14, 2010 Biovex OncoVEX(gm-csf) uses a highly potent oncolytic virus that replicates selectively in tumors and do not replicate in normal cells), destroying cancer cells while leaving surrounding healthy cells unharmed

13 Talimogene laherparepvec (T-VEC) The drug was initially developed by BioVex, Inc. under the name OncoVEX GM-CSF until it was acquired by Amgen in T-VEC was engineered from herpes simplex virus A number of genetic modifications (deletion in both copies of ICP ICP47 disruption) were made to the virus in order to: attenuate the virus ( it can no longer cause herpes) increase selectivity for cancer cells ( it destroys cancer cells while leaving healthy cells unharmed) secrete the cytokine GM-CSF

14 T-VEC Kaufman HL et al., Ann Surg Oncol. 2010;17(3): Núñez MA et al., 2013.

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16 Amgen announced the initial results of the Phase III OPTiM trial on Mar. 19, The objective response rate (any response) with T- VEC was 26%, (11% CR) The most common side effects with T-VEC were fatigue, chills, and fever. No serious side effect occurred in more than 3% of patients in either arm of the study.

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18 Feb. 5, 2014 Amgen And Merck Announce Collaboration To Evaluate Investigational Combination Treatment For Advanced Melanoma About Talimogene Laherparepvec Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumor tissue and to initiate a systemic anti-tumor immune response. Talimogene laherparepvec is injected directly into tumor tissue and is intended to replicate preferentially in tumor cells causing lytic cell death and releasing an array of tumor-derived antigens. Talimogene laherparepvec is also engineered to express granulocyte-macrophage colonystimulating factor (GM-CSF),which can help to activate the immune system. The aim of this combination of actions is to initiate a systemic anti-tumor immune response that targets tumor cells throughout the body. About MK-3475 Many tumors are able to evade the immune system through a mechanism that exploits the PD-1 inhibitory checkpoint protein. MK-3475 is an investigational, highly selective anti-pd-1 immunotherapy designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system's T-cells that target cancer by essentially releasing a brake on the immune system.

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20 Viralytics trial shows Cavatak well-tolerated 12 November, 2012 Cavatak is a proprietary formulation of coxsackievirus A21, is a naturally occurring common cold like virus shown in pre-clinical studies to stimulate in vitro and in vivo oncolytic activity across a range of cancers. The virus achieves this by binding to the N-terminal domain of surface expressed ICAM-1 which is present on the surface of cancers including melanoma, breast and prostate cancers triggering cytosis in the cells. The results of the phase I trial fulfilled the criteria required for Viralytics to advance to a phase II trial under its IND application for the treatment with the US FDA. Viralytics revealed it has so far dosed 13 patients in the phase II melanoma trial, with three of these demonstrating immune-related progression free survival at six months. The primary objective of the trial is progression-free survival in of a targeted 63 melanoma patients. Viralytics also holds the patents to EVATAK, its proprietary formulation of Echovirus Type 1 (EV1). EVI uses a different cell surface receptor to bind and infect cancer cells.

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22 In Latvia «Oncotropism of Viruses and the Problem of Virotherapy of Malignant Tumours» by A. Muceniece published in Riga in 1972

23 Viral Oncolysis in a Model of Mouse Xenografts of Human Angiosarcoma (R. Bruvere 1968) Control 2 days after virus i/m 3 days after virus i/m 4 days after virus i/m 9 days after virus i/m

24 Late Alterations in Melanoma Tissue (R. Bruvere 1969) Before therapy Subcutaneous mts of MM 3 months after therapy with Rigvir (apoptotic tumour cells, lymphocytes, plasma cells)

25 Antibody to Rigvir during the therapy (A. Volrate, R. Garklava 1968)

26 Rigvir ECHO-7 containing medicine for treatment of malignant melanoma was registered in 2004 in Latvia

27 Patients (%) with elevated number of CD16+ cells during the therapy with Rigvir 1 Month 3 Months 6 Months 12 Months Pts (n)

28 Patients (%) with elevated number of CD8+ cells during the therapy with Rigvir Pts (n)

29 Patients (%) with elevated number of CD38+ cells during the therapy with Rigvir 1 Month 3 Months 6 Months 12 Months Pts (n)

30 CD 3+ between malignant melanocytes CD8+ in the lymph node after injections of Rigvir IHC after injection of Rigvir (l/n, Dako, 400х 23/05/2013).

31 Vacuolisation and picnosis of nuclei of malignant melanocytes. H/E. 400x

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33 Female, 62 Melanoma cutis femoris dxt. T4 A N0 M0 Clark V, Breslow 9mm кол-о no. иммуннокомпетентных of immunocompetent cells клеток Ly перeд Rigvir 1 месяц 3 месяца 6 месяцев 12 месяцев Ly CD CD CD CD CD CD CD CD3+ CD4+ CD95+ CD8+ CD38+ CD16+ CD19+

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35 Before the therapy with RIGVIR Melanoma cutis dorsi T4b N2c M0 During the therapy with RIGV IFN Feb 14, 2008 Apr 29, 2010 RIGVIR

36 Male, Melanoma cutis dorsi T4b N2c M0

37 Melanoma cell culture (patient A.S.) D. Pjanova et col Control 24 and 48 h Rigvir 24 and 48 h

38 Cell viability 24h and 48h after treatment with Rigvir MTT - (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test (p<0.05) D. Pjanova et col. 2014

39 Predictive markers? Immune monitoring?

40 Months Rigvir Observation p=0.001 (Log-Rank test)

41 Summary Oncolytic virus therapy has been well tolerated, with largely minor and expected toxicity, and no evidence of uncontrolled or latent infection. A number of clinical trials have combined oncolytic viruses with a second form of therapy. Further investigation will need to focus on optimal selection of viruses, tumor types and stages of disease, viral dose and schedules, routes of delivery. Our data suggest that ECHO-7 containing medicine- Rigvir- is well tolerated and no remarkable side-effects were documented, and significantly better relapse free suvival for stage IB - IIA patients was observed in Rigvir treated group in our retrospective study.

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